-
Nature Oct 2023Effective pandemic preparedness relies on anticipating viral mutations that are able to evade host immune responses to facilitate vaccine and therapeutic design....
Effective pandemic preparedness relies on anticipating viral mutations that are able to evade host immune responses to facilitate vaccine and therapeutic design. However, current strategies for viral evolution prediction are not available early in a pandemic-experimental approaches require host polyclonal antibodies to test against, and existing computational methods draw heavily from current strain prevalence to make reliable predictions of variants of concern. To address this, we developed EVEscape, a generalizable modular framework that combines fitness predictions from a deep learning model of historical sequences with biophysical and structural information. EVEscape quantifies the viral escape potential of mutations at scale and has the advantage of being applicable before surveillance sequencing, experimental scans or three-dimensional structures of antibody complexes are available. We demonstrate that EVEscape, trained on sequences available before 2020, is as accurate as high-throughput experimental scans at anticipating pandemic variation for SARS-CoV-2 and is generalizable to other viruses including influenza, HIV and understudied viruses with pandemic potential such as Lassa and Nipah. We provide continually revised escape scores for all current strains of SARS-CoV-2 and predict probable further mutations to forecast emerging strains as a tool for continuing vaccine development ( evescape.org ).
Topics: Humans; Drug Design; Evolution, Molecular; Forecasting; HIV Infections; Immune Evasion; Influenza, Human; Lassa virus; Mutation; Nipah Virus; Pandemics; SARS-CoV-2; Viral Vaccines; Viruses
PubMed: 37821700
DOI: 10.1038/s41586-023-06617-0 -
Current Opinion in Virology Aug 2019Lassa virus (LASV) is endemic in West Africa, causing an estimated 100000-300000 new infections and up to 5000-10000 deaths yearly. There are no vaccines and... (Review)
Review
Lassa virus (LASV) is endemic in West Africa, causing an estimated 100000-300000 new infections and up to 5000-10000 deaths yearly. There are no vaccines and therapeutics are extremely limited. Typical case fatality rates are ∼1%, although a recent 2018 Nigerian outbreak featured an unprecedented 25.4% case fatality rate. Survivors of infection suffer a lifetime of sequelae with sudden onset sensorineural hearing loss (SNHL) being the most prevalent. The cause of this hearing loss remains unknown, and there is a critical need for further research on its mechanisms and potential therapeutics. The objective of this review is to outline the only currently available small animal model for LASV-induced hearing loss and to identify potential surrogate models.
Topics: Africa, Western; Animals; Disease Models, Animal; Disease Outbreaks; Guinea Pigs; Hearing Loss; Humans; Lassa Fever; Lassa virus; Mice; Mice, Knockout; STAT1 Transcription Factor
PubMed: 31479989
DOI: 10.1016/j.coviro.2019.08.001 -
Scientific Reports Dec 2022Elucidating the adaptive immune characteristics of natural protection to Lassa fever (LF) is vital in designing and selecting optimal vaccine candidates. With...
Elucidating the adaptive immune characteristics of natural protection to Lassa fever (LF) is vital in designing and selecting optimal vaccine candidates. With rejuvenated interest in LF and a call for accelerated research on the Lassa virus (LASV) vaccine, there is a need to define the correlates of natural protective immune responses to LF. Here, we describe cellular and antibody immune responses present in survivors of LF (N = 370) and their exposed contacts (N = 170) in a LASV endemic region in Nigeria. Interestingly, our data showed comparable T cell and binding antibody responses from both survivors and their contacts, while neutralizing antibody responses were primarily seen in the LF survivors and not their contacts. Neutralizing antibody responses were found to be cross-reactive against all five lineages of LASV with a strong bias to Lineage II, the prevalent strain in southern Nigeria. We demonstrated that both T cell and antibody responses were not detectable in peripheral blood after a decade in LF survivors. Notably LF survivors maintained high levels of detectable binding antibody response for six months while their contacts did not. Lastly, as potential vaccine targets, we identified the regions of the LASV Glycoprotein (GP) and Nucleoprotein (NP) that induced the broadest peptide-specific T cell responses. Taken together this data informs immunological readouts and potential benchmarks for clinical trials evaluating LASV vaccine candidates.
Topics: Humans; Lassa virus; Lassa Fever; Nigeria; Immunity, Cellular; Antibodies, Neutralizing; Survivors
PubMed: 36567369
DOI: 10.1038/s41598-022-26045-w -
Drug Design, Development and Therapy 2018Lassa virus (LASV) is a rodent-borne arenavirus endemic to several West African countries that causes Lassa fever (LF). LF is typically mild but it can cause severe... (Review)
Review
Lassa virus (LASV) is a rodent-borne arenavirus endemic to several West African countries that causes Lassa fever (LF). LF is typically mild but it can cause severe disease characterized by hemorrhagic fever and multi-organ failure. A current outbreak of LASV in Nigeria has seen greater than 300 cases with a case fatality rate of 22%. Currently, there are limited treatment options and no vaccine candidates are approved to prevent LASV infection. The Coalition for Epidemic Preparedness Innovations has identified LASV as an emerging pathogen of high consequence and this has resulted in a push for several preclinical vaccine candidates to be advanced toward clinical trials. Here, we discuss several important aspects of LASV infection including immunobiology, immune evasion, and correlates of protection against LF, which have been identified through animal models and human infections. In addition, we discuss several vaccine candidates that have shown efficacy in animal models that could be advanced toward clinical trials. The increased fatality rate seen in the recent LASV outbreak in Nigeria highlights the importance of developing effective treatment and prevention strategies against LF. The spike in LASV cases seen in West Africa has the potential for increased mortality and human-to-human transmission, making the development and testing of effective vaccines for LASV critical.
Topics: Animals; Drug Discovery; Host-Pathogen Interactions; Humans; Lassa Fever; Lassa virus; Nigeria; Viral Vaccines
PubMed: 30147299
DOI: 10.2147/DDDT.S147276 -
Scientific Reports Aug 2023The World Health Organization's R&D Blueprint list of priority diseases for 2022 includes Lassa fever, signifying the need for research and development in emergency...
The World Health Organization's R&D Blueprint list of priority diseases for 2022 includes Lassa fever, signifying the need for research and development in emergency contexts. This disease is caused by the arenavirus Lassa virus (LASV). Being an enveloped virus, LASV should be susceptible to a variety of microbicidal actives, although empirical data to support this expectation are needed. We evaluated the virucidal efficacy of sodium hypochlorite, ethanol, a formulated dual quaternary ammonium compound, an accelerated hydrogen peroxide formulation, and a p-chloro-m-xylenol formulation, per ASTM E1052-20, against LASV engineered to express green fluorescent protein (GFP). A 10-μL volume of virus in tripartite soil (bovine serum albumin, tryptone, and mucin) was combined with 50 μL of disinfectant in suspension for 0.5, 1, 5, or 10 min at 20-25 °C. Neutralized test mixtures were quantified by GFP expression to determine log reduction. Remaining material was passaged on Vero cells to confirm absence of residual infectious virus. Input virus titers of 6.6-8.0 log per assay were completely inactivated by each disinfectant within 1-5 min contact time. The rapid and substantial inactivation of LASV suggests the utility of these microbicides for mitigating spread of infectious virus during Lassa fever outbreaks.
Topics: Animals; Chlorocebus aethiops; Humans; Lassa virus; Lassa Fever; Vero Cells; Anti-Infective Agents; Disinfectants; Green Fluorescent Proteins
PubMed: 37563252
DOI: 10.1038/s41598-023-38954-5 -
Nature Communications Jan 2024Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover,...
Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into LASV neutralization, here we develop a prefusion-stabilized LASV glycoprotein trimer (GPC), pan it against phage libraries comprising single-domain antibodies (nanobodies) from shark and camel, and identify one, D5, which neutralizes LASV. Cryo-EM analyses reveal D5 to recognize a cleavage-dependent site-of-vulnerability at the trimer apex. The recognized site appears specific to GPC intermediates, with protomers lacking full cleavage between GP1 and GP2 subunits. Guinea pig immunizations with the prefusion-stabilized cleavage-intermediate LASV GPC, first as trimer and then as a nanoparticle, induce neutralizing responses, targeting multiple epitopes including that of D5; we identify a neutralizing antibody (GP23) from the immunized guinea pigs. Collectively, our findings define a prefusion-stabilized GPC trimer, reveal an apex-situated site-of-vulnerability, and demonstrate elicitation of LASV-neutralizing responses by a cleavage-intermediate LASV trimer.
Topics: Animals; Guinea Pigs; Lassa virus; Single-Domain Antibodies; Lassa Fever; Antibodies, Viral; Antibodies, Neutralizing
PubMed: 38177144
DOI: 10.1038/s41467-023-44534-y -
PLoS Neglected Tropical Diseases Feb 2018Although an association between Lassa fever (LF) and sudden-onset sensorineural hearing loss (SNHL) was confirmed clinically in 1990, the prevalence of LF-induced SNHL... (Review)
Review
Although an association between Lassa fever (LF) and sudden-onset sensorineural hearing loss (SNHL) was confirmed clinically in 1990, the prevalence of LF-induced SNHL in endemic countries is still underestimated. LF, a viral hemorrhagic fever disease caused by Lassa virus (LASV), is endemic in West Africa, causing an estimated 500,000 cases and 5,000 deaths per year. Sudden-onset SNHL, one complication of LF, occurs in approximately one-third of survivors and constitutes a neglected public health and social burden. In the endemic countries, where access to hearing aids is limited, SNHL results in a decline of the quality of life for those affected. In addition, hearing loss costs Nigeria approximately 43 million dollars per year. The epidemiology of LF-induced SNHL has not been characterized well. The complication of LF induced by SNHL is also an important consideration for vaccine development and treatments. However, research into the mechanism has been hindered by the lack of autopsy samples and relevant small animal models. Recently, the first animal model that mimics the symptoms of SNHL associated with LF was developed. Preliminary data from the new animal model as well as the clinical case studies support the mechanism of immune-mediated injury that causes SNHL in LF patients. This article summarizes clinical findings of hearing loss in LF patients highlighting the association between LASV infection and SNHL as well as the potential mechanism(s) for LF-induced SNHL. Further research is necessary to identify the mechanism and the epidemiology of LF-induced SNHL.
Topics: Africa, Western; Animals; Cost of Illness; Disease Models, Animal; Hearing Loss, Sensorineural; Humans; Lassa Fever; Lassa virus; Mice; Nigeria; Public Health; Quality of Life; Socioeconomic Factors
PubMed: 29470486
DOI: 10.1371/journal.pntd.0006187 -
Viruses Oct 2012Lassa virus (LASV) is the most prominent human pathogen of the Arenaviridae. The virus is transmitted to humans by a rodent reservoir, Mastomys natalensis, and is... (Review)
Review
Lassa virus (LASV) is the most prominent human pathogen of the Arenaviridae. The virus is transmitted to humans by a rodent reservoir, Mastomys natalensis, and is capable of causing lethal Lassa Fever (LF). LASV has the highest human impact of any of the viral hemorrhagic fevers (with the exception of Dengue Fever) with an estimated several hundred thousand infections annually, resulting in thousands of deaths in Western Africa. The sizeable disease burden, numerous imported cases of LF in non-endemic countries, and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. Presently there is no licensed vaccine against LF or approved treatment. Recently, several promising vaccine candidates have been developed which can potentially target different groups at risk. The purpose of this manuscript is to review the LASV pathogenesis and immune mechanisms involved in protection. The current status of pre-clinical development of the advanced vaccine candidates that have been tested in non-human primates will be discussed. Major scientific, manufacturing, and regulatory challenges will also be considered.
Topics: Africa, Western; Animals; Humans; Lassa Fever; Lassa virus; Viral Vaccines
PubMed: 23202493
DOI: 10.3390/v4112514 -
Annals of Clinical Microbiology and... Apr 2021Lassa fever (LF), a zoonotic illness, represents a public health burden in West African countries where the Lassa virus (LASV) circulates among rodents. Human exposure... (Review)
Review
Lassa fever (LF), a zoonotic illness, represents a public health burden in West African countries where the Lassa virus (LASV) circulates among rodents. Human exposure hinges significantly on LASV ecology, which is in turn shaped by various parameters such as weather seasonality and even virus and rodent-host genetics. Furthermore, human behaviour, despite playing a key role in the zoonotic nature of the disease, critically affects either the spread or control of human-to-human transmission. Previous estimations on LF burden date from the 80s and it is unclear how the population expansion and the improvement on diagnostics and surveillance methods have affected such predictions. Although recent data have contributed to the awareness of epidemics, the real impact of LF in West African communities will only be possible with the intensification of interdisciplinary efforts in research and public health approaches. This review discusses the causes and consequences of LF from a One Health perspective, and how the application of this concept can improve the surveillance and control of this disease in West Africa.
Topics: Africa, Western; Animals; Disease Reservoirs; Humans; Lassa Fever; Lassa virus; One Health; Public Health; Rodentia
PubMed: 33894784
DOI: 10.1186/s12941-021-00431-0 -
Nature Communications Dec 2021Lassa virus is endemic in West Africa and can cause severe hemorrhagic fever. The viral L protein transcribes and replicates the RNA genome via its RNA-dependent RNA...
Lassa virus is endemic in West Africa and can cause severe hemorrhagic fever. The viral L protein transcribes and replicates the RNA genome via its RNA-dependent RNA polymerase activity. Here, we present nine cryo-EM structures of the L protein in the apo-, promoter-bound pre-initiation and active RNA synthesis states. We characterize distinct binding pockets for the conserved 3' and 5' promoter RNAs and show how full-promoter binding induces a distinct pre-initiation conformation. In the apo- and early elongation states, the endonuclease is inhibited by two distinct L protein peptides, whereas in the pre-initiation state it is uninhibited. In the early elongation state, a template-product duplex is bound in the active site cavity together with an incoming non-hydrolysable nucleotide and the full C-terminal region of the L protein, including the putative cap-binding domain, is well-ordered. These data advance our mechanistic understanding of how this flexible and multifunctional molecular machine is activated.
Topics: Amino Acid Motifs; Catalytic Domain; Cloning, Molecular; Escherichia coli; Gene Expression; Genetic Vectors; Lassa virus; Models, Molecular; Promoter Regions, Genetic; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; RNA, Viral; RNA-Dependent RNA Polymerase; Recombinant Proteins; Substrate Specificity; Transcription, Genetic; Viral Proteins
PubMed: 34857749
DOI: 10.1038/s41467-021-27305-5